Our laboratory uses biochemical, genetic, and transgenic methods to understand the normal and oncogenic properties of several genes implicated in neoplasia. Current activities address the following issues: (1) The functions of protein-tyrosine kinases. Members of three families of such kinases are under study: (a) Src, Hck, and other members of the Src family that have demonstrated functions in osteoclasts and fibroblasts from genetically altered mice. (B) Sky (Tyro 3), a recently discovered, receptor-type protein-tyrosine kinase from the Axl family, that is abundant in normal brain and mouse mammary tumors. (C) Rlk, a newly discovered member of the Btk/Itk family, expressed exclusively in T cells. (2) Multi-step carcinogenesis. We have used MMTV-Wnt-1 transgenic mice to identify proto-oncogenes (members of the FGF family) and tumor suppressor genes (p53) that influence mammary tumorigenesis. We are attempting to understand the roles of apoptosis, cell cycle control, and telomerase activity in P53-deficient tumors. Unexpectedly, mice with a wild type p53 transgene have a developmental defect of the kidney called oligomeganephronia that results from excessive cell death during renal development. We are also developing a new multi-step tumor model in transgenic mice by recapitulating the lesions found in human gliobastoma. (3) Wnt gene signalling. We are studying the interactions between Wnt proteins and their newly- identified, seven-transmembrane receptors (Frizzled proteins). The roles played by these and several other proteins now implicated in Wnt signaling pathways are being examined in Xenopus and mammalian systems. (4) p16, cdk4 and melanoma. We are cataloging and characterizing mutant forms of p16, an inhibitor of Cdk/cyclin complexes, and of cdk4 that contribute to familial and sporadic melanomas.